The present invention relates to certain novel compounds useful as intermediates for making 16-phenoxy and 16-substituted phenoxy prostatrienoic acid derivatives and a process for making these compounds.
More particularly, the present invention relates to a process for making an enantiomer or racemic mixture of 16-phenoxy and 16-(o, m or p)-substituted phenoxy prostaglandin derivatives represented by the following formula ##STR2## wherein R is hydrogen, lower alkyl or a pharmaceutically acceptable, non-toxic salt of a compound wherein R is hydrogen; X is hydrogen, halo, trifluoromethyl, lower alkyl or lower alkoxy, and the wavy lines represent the .alpha. or .beta. configuration with the proviso that when one wavy line is .alpha. the other is .beta..
The synthesis described herein addresses the twin problems of how to prepare a stereochemically pure enantiomer of the subject compounds while allowing selective deprotection of the C-9 hydroxyl group so it can be oxidized without also oxidizing the C-11 and C-15 groups and that the subsequent deprotetion of C-11 and C-15 will not degrade the resulting molecule.
The problem of preparing a stereochemically pure enantiomer is solved by going through a novel propargyl alcohol intermediate which, though it is made as a stereochamical mixture, can be separated into its two stereochemially pure isomers. One isomer of this stereochemically pure propargyl alcohol is then converted to a single, stereochemically pure allenic compound by employing a stereospecific homologation/rearrangement reaction in the next step. By starting with a specific stereochemically pure phenoxy lactone compound, which is available in the art, one can open the lactone and convert the resulting acid to an aldehyde. This novel aldehyde is reacted a metal ethynyl to give a propargyl alcohol having two stereo isomers. The two isomers can be is seperated into two stereochemically pure fractions by chromatagraphic means where one has properly selected the ether-forming protecting groups at C-9, C-11 and C-15, particularly at C-9. It has been found that a bulky ether-forming group at C-9 is necessary to effect readily this separation. For example, when the C-9 hydroxyl protecting group is an appropriate alkyl, aryl or arylalkyl substituted silyl ether, separation of the two propargyl alcohol isomers may be readily effected where otherwise separation is usually difficult and incomplete. The second essential step is to convert one stereochemically pure isomer to a single stereochemically pure allene-containing compound. This is accomplished by a homologation/rearrangement reaction using a trialkyl orthoacetate reagent and temperature.
The other problem is to design a synthetic sequence which will allow selective deprotection of the C-9 hydroxyl group so it can be oxidized, then drop off the C-11 and C-15 hydroxyl protecting groups without decomposing the resulting molecule. This is accomplished here by protecting C-9 with a base-labile ether-forming group while protecting C-11 and C-15 with base-stabile ether-forming groups. Then it is possible to drop off the C-9 protecting group, oxidize the hydroxyl group and then deprotect C-11 and C-15 under mild acid conditions. This sequence is essential because base will cause rearrangement of the stereochemistry C-8 and catalytic hydrogenation will effect the allene group.